Skin cancer, the most common form of cancer, is comprised of keratinocyte cancers (basal and squamous cell carcinomas), which are derived from the epithelial tissues of the skin; and melanoma, which is derived from pigment-producing melanocytes that reside in the skin and other parts of the body. Melanoma accounts for less than 5% of skin cancers but is responsible for 80% of skin cancer-related deaths. If diagnosed early at a cutaneous localized stage, surgical resection can usually cure the disease. Thus for stage I melanoma the prognosis is fairly good, with a five year survival rate of over 90%. However, the prognosis worsens the deeper the lesion extends beneath the skin because of melanoma's propensity to invade and metastasize. Metastatic melanoma remains one of the most difficult cancers to treat and surgical resection is not generally a curative treatment option. The five year survival rate for Stage IV melanoma is 15% to 20%. Worldwide, the incidence of melanoma has increased at an alarming rate, with a lifetime risk of developing melanoma as high as 1/58 for males in the U.S. to 1/25 for males in Australia. The increased incidence in recent decades is partly explained by altered sun exposure habits of the population, but several hereditary risk factors are also known.
The development of melanoma is complex and is related to environmental and genetic factors. Pigmentary characteristics are strongly correlated with melanoma incidence, with a higher risk in Type I skin types than Type VI skin types as defined by the Fitzpatrick scale. Other important risk factors are the number of pigment nevi (common moles), the number of dysplastic nevi and familial history of malignant melanomas. Mutations in the MAPK pathway have been shown to be very important in melanoma development; up to 90% of melanomas and benign melanocytic neoplasms carry activating mutations in either BRAF or NRAS. BRAF mutations occur in approximately 50% of primary cutaneous melanomas and up to 70% of malignant melanomas (Thomas et al., 2004, PMID: 15140228), where 80% of those mutations are a valine to glutamate change at position 600 (V600E) (Davies et al., 2002, PMID: 12068308.) NRAS mutations occur in approximately 20% of primary cutaneous melanomas. Recently developed treatments for melanoma have focused on these common genetic mutations that are associated with melanoma, e.g vemurafenib for BRAF V600E mutations. However, such therapeutics are ineffective on melanomas that are not characterized by the specific mutation. Furthermore many of these therapeutics provide some short term benefit but, for the most part, fail to provide a lasting cure that is free of tumor relapse or recurrence. There remains a great need to develop therapies that can be used to treat melanomas with various mutational characteristics and which provide a sustained remission.